Retinoic acid (RA) and some of its analogs (retinoids) can a) suppress or reverse the transformation of premalignant cells to the malignant state, b) effect the regression of epithelial papillomas induced by carcinogens in experimental animals, and c) inhibit the tumor-promotion activity of phorbol esters. Because RA damages lysozomal membranes and is systemically toxic, retinoids with a better therapeutic ration are needed. In a joint experimental and theroretical effort, we propose to synthesize and screen potentially more effective retinoids for the chemoprevention and treatment of epithelial cancer and to calculate their conformational and electronic structures. In particular, we propose systematic structure-activity studies of a series of analogs of two very active retinoids, 4-(2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl)-1E-propen-l-yl)benz oic acid and 4-(2,6,6-trimethyl-1-cyclohexen-l-yl)-1E-3E-butadien-l-yl)benzoic acid, to a) determine what regions of these molecules affect tumor-inhibitory activiy and toxicity,and b) identify what steric and electronic modifications can be made to enhance tumor-inhibitory activity or reduce toxicity so that compounds having a mroe favorable therapeutic ration may be synthesized. The first compound is farmore active than RA, and the second is comparable to retinoic acid in activity. However, both are far more toxic than RA--hence the need for analogs having better therapeutic ratios. We will investigate the effect on activity and toxicity of steric and electronic modifications of three regions: 1) the 4-position and 2) the aromatic ring of the tetrahydronaphthalene ring system, and 3) the benzoic acid ring. The therapeutic ratio of thes compounds will be determined through in vivo aantipapilloma (tumor-inhibitory) and hypervitaminosis A (toxicity) assays. Conformational and electronic structural properties of these analogs will be calculated using quantum mechanical methods to identify fundamental molecular properties that could serve as reliable discriminating indicators of tumor-inhibitory activity and toxicity. This comprehensive approach should lead to the design and synthesis of retinoids having an optimal therapeutic ratio.